http://repub.eur.nl/res/aut/2995/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/30208/ 2008-12-01T00:00:00Z The few loci associated with multiple sclerosis (MS) are all related to immune function. We report a GWA study identifying a new locus replicated in 2,679 cases and 3,125 controls. An rs10492972[C] variant located in the KIF1B gene was associated with MS with an odds ratio of 1.35 (P = 2.5 × 10-10). KIF1B is a neuronally expressed gene plausibly implicated in the irreversible axonal loss characterizing MS in the long term. http://repub.eur.nl/res/pub/30248/ 2008-08-01T00:00:00Z The genetic basis of major depressive disorder (MDD) has been investigated extensively, but the identification of MDD genes has been hampered by conflicting results from underpowered studies. We review all MDD case-control genetic association studies published before June 2007 and perform meta-analyses for polymorphisms that had been investigated in at least three studies. The study selection and data extraction were performed in duplicate by two independent investigators. The 183 papers that met our criteria studied 393 polymorphisms in 102 genes. Twenty-two polymorphisms (6%) were investigated in at least three studies. Seven polymorphisms had been evaluated in previous meta-analyses, 5 of these had new data available. Hence, we performed meta-analyses for 20 polymorphisms in 18 genes. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistically significant associations were found for the APOE ε2 (OR, 0.51), GNB3 825T (OR, 1.38), MTHFR 677T (OR, 1.20), SLC6A4 44 bp Ins/Del S (OR, 1.11) alleles and the SLC6A3 40 bpVNTR 9/10 genotype (OR, 2.06). To date, there is statistically significant evidence for six MDD susceptibility genes (APOE, DRD4, GNB3, MTHFR, SLC6A3 and SLC6A4). http://repub.eur.nl/res/pub/8490/ 2005-01-01T00:00:00Z We obtained conclusive linkage of Alzheimer disease (AD) with a candidate region of 19.7 cM at 7q36 in an extended multiplex family, family 1270, ascertained in a population-based study of early-onset AD in the northern Netherlands. Single-nucleotide polymorphism and haplotype association analyses of a Dutch patient-control sample further supported the linkage at 7q36. In addition, we identified a shared haplotype at 7q36 between family 1270 and three of six multiplex AD-affected families from the same geographical region, which is indicative of a founder effect and defines a priority region of 9.3 cM. Mutation analysis of coding exons of 29 candidate genes identified one linked synonymous mutation, g.38030G-->C in exon 10, that affected codon 626 of the PAX transactivation domain interacting protein gene (PAXIP1). It remains to be determined whether PAXIP1 has a functional role in the expression of AD in family 1270 or whether another mutation at this locus explains the observed linkage and sharing. Together, our linkage data from the informative family 1270 and the association data in the population-based early-onset AD patient-control sample strongly support the identification of a novel AD locus at 7q36 and re-emphasize the genetic heterogeneity of AD. http://repub.eur.nl/res/pub/5912/ 2004-03-01T00:00:00Z Increasing amounts of data suggest that affective disorders might be related to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, one of the stress-response systems. Arginine vasopressin (AVP) influences several symptoms, relevant to affective disorders, notable memory processes, pain sensitivity, synchronization of biological rhythms and the timing and quality of REM sleep. We examined whether genetic variations in the AVP receptor 1b gene (AVPR1b) could be associated with increased susceptibility to affective disorders using a gene-based association analysis of single-nucleotide polymorphisms (SNPs). Five SNPs were identified in AVPR1b and genotyped in two well-diagnosed samples of patients with recurrent major depression and matched controls. In the Swedish sample, we observed significant allele (P=0.02) and genotype (P=0.01) association with SNP AVPR1b-s3, and in the Belgian sample, a borderline significant association with SNP AVPR1b-s5 (P=0.04). In both patient-control samples, the haplotype defined by alleles A-T-C-A-G for the AVPR1b-s SNPs s1-s2-s3-s4-s5 was significantly over-represented in controls compared to patients. Our data support a protective effect of this major haplotype for recurrent major depression. http://repub.eur.nl/res/pub/9244/ 2000-01-01T00:00:00Z Mutations in the presenilin 1 ( PSEN1 ) gene have been implicated in 18-50% of autosomal dominant cases with early-onset Alzheimer's disease (EOAD). Also, PSEN1 has been suggested as a potential risk gene in late-onset AD cases. We recently showed genetic association in a population-based study of EOAD, pointing to the 5' regulatory region of PSEN1. In this study we systematically screened 3.5 kb of the PSEN1 upstream region and found four novel polymorphisms. Genetic analysis confirmed association of two polymorphisms with increased risk for EOAD. In addition, we detected two different mutations in EOAD cases at-280 and-2818 relative to the transcription initiation site in exon 1A of PSEN1. Analysis of the mutant and wild-type-280 variants using luciferase reporter gene expression in transiently transfected neuroblastoma cells showed a 30% decrease in transcriptional activity for the mutant-280G PSEN1 promoter variant compared with the wild-type variant-280C. Our data suggest that the increased risk for EOAD associated with PSEN1 may result from genetic variations in the regulatory region leading to altered expression levels of the PSEN1 protein.